Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.
Doing a bit of work on this the Hallmarks of aging (original version) are:
genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
The paper says:
We find evidence that, in post-mitotic tissues, cryptic mutations can evade negative selection, expanding neutrally, and are linked to 5 of 9 hallmarks of ageing2 (genomic instability, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, and altered intercellular communication);
That leaves: (with my comments)
telomere attrition -
Much of senescence is not driven by replicative senescence, longer telomeres are created by telomerase which also acts to improve mitochondria and is linked to higher acetylation levels (higher energy levels). Hence telomere attrition is part of this.
epigenetic alterations
The problems with mitochondria affects the Mitochondrial membrane potential and the rate at which citrate passes into the cytosol. That directly drives acetyl-CoA levels and following that you get acetylation both of the histone and of splicing factors. Perhaps this is the biggest thing missing from the paper.
cellular senescence and
stem cell exhaustion
IMO the main cause of cellular senescence is when stem cells fail to differentiate as a result of inefficient mitochondria (and the feedback system from SASP which reduces SLC25A1). This results in stem cell exhaustion as well as the cells basically get stuck part way through differentiation.